This K23 proposal will enable Jason W. Smith, MD, to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. Dr. Smith will conduct a prospective clinical study evaluating the effects of adjunctive direct peritoneal resuscitation (DPR) on patients undergoing damage control surgery and hemorrhagic shock. Highlights of Dr. Smith's career development plan include: (1) obtaining a PhD in Physiology and Biophysics focusing on microcirculation and hemorrhagic shock, (2) experience running a prospective clinical trial at a large academic hospital, and (3) technical laboratory training in experimental methods that can be applied across a wide range of future experiment subjects. These activities will occur in the setting of the University of Louisville and the University Of Louisville Hospital Trauma Institute and will be monitored quarterly by an advisory committee. An estimated 46 million Americans suffer a traumatic accident yearly. A number of those patients will suffer hemorrhagic shock and its sequelae as a result of their injury. Our preliminary data document (i) improvement in patient outcomes using adjunctive peritoneal resuscitation, and (ii) improvement in liver blood flow after administration of DPR. Our hypothesis is that DPR therapy will result in improvement in mechanisms postulated to play a role in the development and progression of systemic inflammatory response due to hemorrhagic shock. To test this hypothesis, we will perform a prospective randomized controlled, mechanistic study of DPR administration in 100 patients undergoing damage control surgery for hemorrhagic shock over a 30 month period. The expected primary endpoints are an (i) increase in hepatic blood flow during resuscitation in patients treated with DPR , (ii) reduction in cellular edema and hepatocyte necrosis similar to our laboratory findings, and (iii) a reduction inflammatory response and chemotactic mediators compared to the conventional resuscitation group. Additionally, expected secondary clinical endpoints are (i) improved timeto abdominal closure, (ii) decreased fluid resuscitation requirements with decreased vascular permeability, and (iii) a reduction in post-operative complications following damage control surgery. These studies utilize state of-the art well validated techniques in a translational approach to develop an enhanced understanding of a potential innovativetherapy for hemorrhagic shock.